1. Field of the Invention
This invention relates to indolecarboxamide derivatives which selectively bind to brain dopamine receptor subtypes. More specifically, it relates to fused indolecarboxamides such as carbozolecarboxamides, tetrahydrocarbazolecarboxamides, and fused cycloalkylindolecarboxamides, and to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in the treatment or prevention of various neuropsychochological disorders such as schizophrenia and other central nervous system diseases.
2 Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D.sub.2 receptors in the striatal region of the brain. The dopamine D.sub.3 receptor subtype has recently been identified (Sokoloff et al., Nature, 347, 146 (1990)). Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D.sub.3 receptor may play a major role in the etiology of schizophrenia. Selective D.sub.3 antagonists may be effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds of the present invention demonstrate high affinity and selectivity in binding to the D.sub.3 receptor subtype. They may be of potential use in treatment of schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias may also be treated directly or indirectly by modulation of D.sub.3 receptors.
U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides said to have affinity at dopamine D.sub.3 receptors. The compounds of the present invention differ significantly from this prior art in that they possess a dibenzofurancarboxamide substructure.
U.S. Pat. No. 3,932,456 discloses compounds of the formula: ##STR3##
wherein each of R.sub.1 and R.sub.2 is hydrogen, (lower)alkyl, cycloalkyl of 3 to 6 ring carbon atoms, alkenyl of 3 to 6 carbon atoms having the vinyl unsaturation in other than the 1-position of the alkenyl group, or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached is pyrrolidino, piperidino, N-(lower) alkylpiperazino, or morpholino; each A is alkylene of 2 to about 8 carbon atoms and separates its adjacent Y and amino nitrogen by an alkylene chain of at least 2 carbon atoms; each Y is oxygen, or N--R wherein R is hydrogen, methyl or ethyl; and R.sub.3 is hydrogen or (lower) primary or secondary alkyl; or a pharmaceutically acceptable acid addition salt thereof. These compounds are said to be useful as pharmaceuticals for preventing or inhibiting a viral infection PA1 wherein R.sub.1 represents halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, NO.sub.2, --NR.sub.4 R.sub.5, R.sub.4 R.sub.5 NCO(CH2).sub.m --, R.sub.4 R.sub.5 NSO.sub.2 (CH2).sub.m --, R.sub.6 CONH(CH2).sub.m --or R.sub.7 SO.sub.2 (CH2).sub.m --; R.sub.4 and R.sub.5 each independently represent hydrogen or C.sub.1 -C.sub.4 alkyl or N.sub.4 R.sub.5 represents a 5- to 7-member heterocyclic ring; R.sub.6 represents hydrogen or C.sub.1 -C.sub.4 alkyl; R.sub.7 represents C.sub.1 -C.sub.4 alkyl; m is zero, 1, or 2; n is zero or 1 to 5; R.sub.2 and R.sub.3 each independently represent hydrogen, C.sub.1 -C.sub.6 alkyl or benzyl or --NR.sub.2 R.sub.3 represents a pyrrolidino, piperidino or hexahydroazepino ring; and A represents a bond, a C.sub.1 -C.sub.5 alkylene chain or a C.sub.1 -C.sub.5 alkenyl chain wherein the double bond is not adjacent the nitrogen atom. Murray et al., Bioorg. Med. Chem. Let., 5: 219 (1995), describe 4carboxarnido-biphenyls said to have affinity at dopamine D.sub.3 receptors. PA1 where R.sub.a and R.sub.b independently represent hydrogen, C.sub.1 -C.sub.6 alkyl, hydroxy, C.sub.1 -C.sub.6 alkoxy, or amino mono- or disubstituted with C.sub.1 -C.sub.6 alkyl; and PA1 n is an integer from one to four; PA1 R.sub.1 and R.sub.2 are the same or different and represent hydrogen, C.sub.1 -C.sub.6 alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.6 alkoxy, --O.sub.2 CR', --NHCOR', --COR', or --SO.sub.m R', where R' is C.sub.1 -C.sub.6 alkyl and where m is 0, 1 or 2; or PA1 R.sub.1 and R.sub.2 independently represent --CONR'R" or --NR'R" where R' and R" independently represent hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 R.sub.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, or --COR'" where R'" is C.sub.1 -C.sub.6 alkyl; PA1 R.sub.4 is hydrogen or C.sub.1 -C.sub.6 alkyl; and PA1 R represents an azacycloalkylalkyl group. PA1 the A ring, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as defined above for Formula I; and PA1 R.sub.p represents an azacycloalkylalkyl group of the formula ##STR8## PA1 where PA1 the A ring and R.sub.1 -R.sub.6 are as defined above for Formula IA; and PA1 Q, Z and W are as defined above. PA1 where Z and W are defined above. PA1 where W is defined above. PA1 where Z and W are defined above and R.sub.5 and R.sub.6 together with the 6-membered ring to which they are attached form a 5 to 8-membered ring. In such cases, and where Z is nitrogen, the resulting group is a diazabicyclo group. Examples include 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 2,5-diazabicyclo[2.2.2]octane, 7.9-diazabicyclo[4.2.2]decane, and 3,9-diazabicyclo[3.3.1]nonane. PA1 where R.sub.c and R.sub.d independently represent hydrogen or a group of the formula ##STR22## PA1 R, R.sub.3, and R.sub.4 are defined in the table. PA1 wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, A, Q, Z and W are defined as above for Formula I. PA1 wherein R.sub.a, R.sub.b, R.sub.1, R.sub.2 and n are defined as above, may be prepared by reacting a compound of Formula Va1 with a compound of Formula Va2 via the Fischer indole synthesis as shown below: ##STR55## PA1 wherein R.sub.a, R.sub.b, R.sub.1, R.sub.2 and n are defined as above. PA1 wherein R.sub.a and R.sub.b are defined as above for Formula I, may be prepared by dehydrogenation of a compound of Formula Vb1 as shown in the below scheme in a refluxing solvent such as, for example, xylene, in the presence of a catalyst such as palladium on carbon or the like. Preferably, the reaction is carried out with 10% palladium on carbon in xylene at reflux for about eight hours. ##STR58## PA1 wherein R.sub.a and R.sub.b are defined as above for Formula I, may be prepared by reacting a compound of Formula Vb2 with a compound of Formula Vb3 via the Fischer indole synthesis as represented below: ##STR60## PA1 wherein R.sub.a and R.sub.b are defined as above for Formula I. The reaction may be carried out according to well known literature procedures. See, for example, Robinson, "The Fischer Indole Synthesis", Wiley, N.Y., 1983. Preferably, the above reaction is carried out in the presence of acetic acid (HOAC) under reflux for about 4 hours. PA1 wherein R.sub.1, R.sub.2 and A are defined as above and R.sub.3 is hydrogen, may be prepared by methods analogous to those described above for Formula Va or those for Formula Vb. PA1 wherein R.sub.1, R.sub.2 and A are defined as above with a halide of the formula: R.sub.3 -X, where R.sub.3 is defined as above for Formula I and X is a ride. The reaction is normally carried out in the presence of a base such as, for example, K.sub.2 CO.sub.3 in a solvent such as acetone or the like at room temperature. Subsequently, the resulting intermediate may be hydrolyzed with a base such as NaOH or the like in an aqueous solvent such as methanol at about 50.degree. C. to afford a compound of Formula V. Preferably, the reaction is carried out with K.sub.2 CO.sub.3 in acetone, and the hydrolysis is carried out with NaOH in aqueous methanol.
International application WO94/14773 discloses compounds said to have affinity for the 5-HT.sub.1 -like receptor and utility in the treatment of migraine. The compounds disclosed in that application have the following formula: ##STR4##